The recently developed techniques of MRI (magnetic resonance imaging) or NMR (nuclear magnetic resonance) imaging encompasses the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. In current use, the images produced constitute a map of the distribution density of protons and/or their relaxation times in organs and tissues. The MRI technique is advantageously non-invasive as it avoids the use of ionizing radiation.
While the phenomenon of NMR was discovered in 1945, it is only respectively recently that it has found application as a means of mapping the internal structure of the body as a result of the original suggestion of Lauterbur (Nature, 242, 190-191, 1973). The lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. Additionally, any scan plane can readily be selected including transverse, coronal, and sagittal sections.
In an NMR experiment, the nuclei under study in a sample (e.g. protons) are irradiated with the appropriate radio-frequency (RF) energy in a highly uniform magnetic field. These nuclei, as they relax, subsequently emit RF radiation at a sharp resonant frequency. The emitted frequency (RF) of the nuclei depends on the applied magnetic field.
According to known principles, nuclei with appropriate spin when placed in an applied magnetic field [B, expressed generally in units of gauss or tesla (10&lt;4&gt;gauss)] align in the direction of the field. In the case of fluorine, these nuclei precess at a frequency f=94.08 MHz at a field strength of 2.35 Tesla. At this frequency, an RF pulse of radiation will excite the nuclei and can be considered to tip the nuclei out of the field direction, the extent of this rotation being determined by the pulse duration and energy. After the RF pulse, the nuclei "relax" or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency. The decay of the signal is characterized by two relaxation times, i.e., T1, the spin-lattice relaxation time or longitudinal relaxation time, that is, time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T2, the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins. These relaxation times have been established for various fluids, organs and tissues in different species of mammals.
In MRI, scanning planes and slice thickness can be selected without loss of resolution. This permits high quality transverse, coronal and sagittal images to be obtained directly. The absence of any moving parts in MRI equipment promotes a high reliability. It is believed that MRI or NMR imaging has a greater potential than CT for the selective examination of tissue characteristics in view of the fact that in CT, X-ray attenuation coefficients alone determine image contrast, whereas at least four separate variables (T1, T2, nuclear spin density and flow) may contribute to the NMR signal. For example, it has been shown (Damadian, Science, Vol. 171, p. 1151, 1971) that the values of the T1 and T2 relaxation in tissues are generally longer by about a factor of 2 in excised specimens of neoplastic tissue compared with the host tissue.
By reason of its sensitivity to subtle physio-chemical differences between organs and/or tissues, it is believed that MRI may be capable of differentiating tissue types and in detecting diseases which induce physicochemical changes that may not be detected by X-ray or CT which are only sensitive to differences in the electron density of tissue. The images obtainable by MRI techniques also enable the physician to detect structures smaller than those detectable by CT and thereby provide comparable or better spatial resolution.
The use of perfluorocarbon compounds in various diagnostic imaging technologies such as ultrasound, magnetic resonance, radiography and computed tomography, has been set forth in an article by Robert F. Mattrey in SPIE, Volume 626, Medicine, XIV/PACS IV (1986), pages 18-23 .
Magnetic resonance imaging of liver tumor and rats using perfluorochemcial emulsions was reported in "In Vivo .sup.19 F NMR Imaging of Liver, Tumor and Abcess in Rats", H. E. Longmaid III, et al., INVESTIGATIVE RADIOLOGY, March -April 1985, Vol. 20, p. 141-144. The compounds utilized displayed multiple peak NMR spectra.
Imaging of brain tumors with perfluorooctyl bromide has been described in "Brain-Tumor Imaging Using Radiopaque Perfluorocarbon", Nicholas J. Patronas, M.D., et al. JOURNAL OF NEUROSURGERY, May 1983, Vol. 58, pp. 650-653.
Ultrasound imaging of organs has been enhanced by FLUOSOL-DA (perfluorodecalin and perfluorotripropylamine) as reported in "Perfluorochemicals as U. Contrast Agents for Tumor Imaging and Hepatosplenography: Preliminary Clinical Results", Robert F. Mattrey, M.D., et al., RADIOLOGY, May 1987, Vol. 163, No. 2, pp. 339-343.
In European published Patent Application 0 118 281, published Sep. 12, 1984, a technique for the detection of gas in an animal is set forth using nuclear magnetic resonance techniques embodying various fluorochemical agents. Among the fluorochemical agents there is included perfluoro ether polymer (Fomblin Y/01).
In U.S. Pat. No. 4,523,039 the production of fluorocarbon ethers of various structures is set forth wherein the resulting fluorocarbon ether produces a noncyclic structure.
U.S. Pat. No. 4,570,004 describes a method of production and a composition of matter including perfluoro 15-crown-5 ether. The patent identifies that the crown ethers in general can be useful as oxygen carriers and various biomedical products.
U.S. Pat. No. 4,639,364 discloses the use of various fluorine-containing compounds for magnetic resonance imaging.
In parallel to the progress that has been made in the use of Magnetic Resonance Imaging (MRI) as a clinical tool, in vivo NMR spectroscopy (also called magnetic resonance spectroscopy, or MRS), has been developed to probe human body chemistry noninvasively. Efforts are being made to correlate the changes that are observed in an NMR spectrum, such as the changes in chemical shifts and areas of resonance peaks, to biochemical and metabolical states of diseased organs. For example, knowledge of the concentrations of high energy metabolites, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), phosphocreatine (PC.sub.r), and inorganic phosphate (Pi) derived from phosphorous (.sup.31 P) NMR, can be used to determine whether or not a tissue is ischemic. It is also known that tumors do affect the cell metabolism. By monitoring the changes in the spectral features of the tumor, due to the radiation treatments, it is possible to observe a patient's progress without performing repeated biopsies. Progress has also been made in monitoring the metabolic heterogeneity within a tumor by in vivo human spectroscopy. The clinical applications are not limited to these examples, but are mentioned in order to demonstrate that in vivo human spectroscopy has potential future clinical applications.
Today, the technology is still evolving. At this point, techniques must be developed to define the volume of interest (VOI) to ensure that the spectrum obtained is from the smallest region of interest and not from the surrounding tissue. Therefore, the technological challenge is to develop protocols which define controlled localized diseased areas, which will definitely have an impact on the early use of in vivo NMR spectroscopy as a routine clinical method for diagnostic purposes. In addition to the need for accuracy of localization, other desired features of an NMR spectrometer for clinical applications are to provide: 1) the best sensitivity per unit time, per unit volume; 2) the minimum of experimental time; and 3) ease of operation.
The identified needs of a MRS perfluorchemical are for it to be: 1) biocompatible and non-toxic; 2) having all fluorine atoms of equivalent magnetic resonance; 3) have a T.sub.1 relaxation time highly responsive to dissolved oxygen and not paramagnetic ions; and 4) be cost effective.
Of the important nuclei in vivo spectroscopy, .sup.31 P remains the most popular, since it offers a noninvasive, nondisruptive method for providing information on the vital role of phosphorous in many aspects of life processes. For example, .sup.31 P NMR signals provide information on cellular energetics: phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi). ATP has been referred to as the "universal currency of free energy" in the human body, mainly because of its widespread use as a carrier of free energy within a cell. .sup.31 P NMR also provides information concerning phospholipid syntheses and degradation, and also synthesis of glycoproteins/glycolipids. It also permits the measurement, invasively, of intracellular pH to indicate the acid/alkaline state of the tissue. These measurements are useful in understanding the state of health of tissues. Furthermore, the increase or decrease of .sup.31 P resonance signal intensities of an intact tissue is useful in probing the biochemical and pathological aspects of diseased tissues. The changes in spectral patterns can be used to diagnose and monitor the treatment for a particular disease.
Parhamic and Fung established the characteristics of enhanced .sup.19 F relaxation due to molecular oxygen and were one of the first to foresee the possibility of using .sup.19 F NMR for in situ determination of the amount of oxygen dissolved in body fluids, organic or clinical studies. They investigated the current important fluorochemicals such as cis- and trans-perfluorodecalin and perfluorotributylamine. The logitudinal relaxation time (1/T.sub.1) of each fluorine nuclei depended linearly on the partial pressure of oxygen. The slopes of their plots were different for each type of fluorine atom in the perfluorochemical. They reasoned steric effects rather than specific binding of molecular oxygen was the cause. P. Parhami and B. M. Fung, Fluorine-19 Relaxation Study of Perfluoro Chemicals as Oxygen Carriers, J. Physical Chemicals, 1983 pp 1928-1931.
Nunnally et al. showed that .sup.19 F-NMR spectra can be used to monitor the rate of blood pool and extravascular space dilution of a single bolus injection using emulsified fluorine species. Their data were the first results of in vivo .sup.19 F-NMR studies of perfusion and the determination of metabolism in specific organs using .sup.19 F-NMR. R. L. Nunnally, R. M. Peshock, R. B. Rehr, Fluorine-19 (.sup.19 F) NMR In Vivo. Potential For Flow And Perfusion o Measurements, Proceeding of the Society of Magnetic Resonance in Medicine, Second Annual Meeting Aug. 16-19, 1983 pg. 266.
In 1985 Reid et al. established that in a mixed fluorocarbon emulsion the spin-lattice relaxation rates of the component .sup.19 F spectral lines were highly sensitive to oxygen concentration. R. S. Reid, C. J. Koch, M. E. Castro, E. O. Trisben, D. J. P. Boisvert and P. S. Allen. The Influence Of Oxygenation On The .sup.19 -Spin Lattice Relaxation Rates Of Fluosol DA, Phys. Med. Biol. Vol 30 No. 7, pp. 677-686 1985.
Wyrwicz et al. have shown that by using .sup.19 F-NMR spectroscopy they can detect small amounts (100-500 micromolar) of fluorinated anesthetics in the brain of live animals during and after anesthesia. A. M. Wyrwics, M. H. Pszenny, J. C. Schofield, R. E. Gordon and P. A. Martin, Observations Of Fluorinated Anesthetics In Rabbit Porain by .sup.19 F-NMR, Proceedings of the Society of Magnetic Resonance in Medicine, Second Annual Meeting, Aug. 16-19, 183 pp 381-382.
Clark, et al. showed, under their conditions, the .sup.19 F-NMR spectrum of perfluordecalin in emulsion, is not interfered with from liver tissue. They found that perfluorochemical T.sub.1 relaxation times are insensitive to paramagnetic ions. L. C. Clark, J. L. Ackerman, S. R. Thomas, R. W. Millard, R. E. Hoffman, R. G. Pratt, H. Ragle-Cole, R. A. Kinsey and R. Janakiruman, Perfluorinated Organic Liquids And Emulsions As Biocompatible NMR Imaging Agents For .sup.19 F And Dissolved Oxygen, Adv. Exp. Med. Biol. Vol. 180(6) pp 835-845, 1984.
The prior art, despite its suggestion for the use of magnetic resonance spectroscopy for medical and biodiagnostic purposes and the prior art's suggestion of various fluorine-containing compounds for use as agents in nuclear magnetic resonance spectroscopy, has failed to provide a particularly sensitive fluorine agent for nuclear magnetic resonance spectroscopy which provides high signal to noise ratios sufficient for detailed diagnosis of deep tissue structures and unexpectedly high and diagnostically useful NMR signal response to the presence to oxygen.